Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, United States.
Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
J Org Chem. 2022 Aug 19;87(16):11204-11217. doi: 10.1021/acs.joc.2c01530. Epub 2022 Aug 5.
The α-methylene-γ-lactam offers promise as a complementary warhead for the development of targeted covalent inhibitors. However, an understanding of the factors governing its electrophilic reactivity is needed to promote the development of lead compounds utilizing this motif. Herein we synthesize a series of -aryl-substituted α-methylene-γ-lactams installed within the framework of a bioactive guaianolide analog. To determine the effects of the guaianolide structure on the electrophilic reactivity, these compounds were reacted with glutathione under biomimetic conditions, and the rate constants were measured. A linear free-energy relationship was observed with the Hammett parameter of the -aryl group within the - or -annulated isomeric series of compounds. However, the -annulated compounds exhibited a ca. 10-fold increase in reactivity relative to both the -annulated compounds and the corresponding -arylated 3-methylene-2-pyrrolidinones. Density functional theory calculations revealed that the reactivity of the -annulated stereoisomers is promoted by the partial release of the ring strain of the fused seven-membered ring in the thio-Michael addition transition state.
α-亚甲基-γ-内酰胺作为靶向共价抑制剂开发的补充弹头具有一定的应用前景。然而，为了促进利用这一结构的先导化合物的发展，需要了解控制其亲电性反应性的因素。本文通过生物活性愈创木烷内酯类似物的结构，合成了一系列取代的 α-亚甲基-γ-内酰胺。为了确定愈创木烷内酯结构对亲电性反应性的影响，在生物模拟条件下使这些化合物与谷胱甘肽反应，并测定了反应速率常数。在 -或 -稠合的异构系列化合物中，观察到与 -芳基取代基的哈米特参数之间存在线性自由能关系。然而，与 -稠合的化合物以及相应的 -芳基取代的 3-亚甲基-2-吡咯烷酮相比，-稠合的化合物的反应性约增加了 10 倍。密度泛函理论计算表明，在硫代-Michael 加成过渡态中，稠合的七元环的部分环张力释放促进了 -稠合立体异构体的反应性。
